Serial electrical stimulations of hypothalamic orexin-containing neuronal regions lead to elevation of CSF OrexinA concentration and fasten the recovery of sleep-wakefulness cycle from experimentally induced comatose state

Abstract

Study is aimed at assessing the Hypothalamic Orexinergic system as the neuronal substrate that increases the speed of regulation of disturbed sleep homeostasis and wakefulness recovery from some pathological conditions, namely from experimental comatose state. Pre-clinical evidences on this topic is sparse and we are studying this question for the first time. Using white wild rats, ( n = 12) modeling of semi-chronic experimental comatose state was induced by kainic and/or ibotenic acid lesion of intra-collicular layers. EEG registration was started immediately, lasting continuously for 72 h. 30 min after comatose state, serial electrical stimulations (8–12v, 200c/s, 0.1 ms) of dorsal, lateral, posterior and perifornical Hypothalamic Orexin- containing neurons began. Stimulation periods, lasting for 1 h, with 5 min intervals between subsequent stimulation, were applied in turn to the left and to the right side hypothalamic regions. CSF OrexinA concentration was measured by ELISA method. Statistical processing was made by Students’ t -test. Kainic and/or ibotenic lesioning of intra-collicular layers wholly disrupts cyclic alternation of sleep-wakefulness cycle (SWC) behavioral states. Isolated forebrain falls into comatose state and pathological pattern of electrical activity (exaggerated spindle activity with strongly desynchronized inter-spindle periods) takes the dominant position in neo- and paleo-cortical structures. Dominance of this pathological pattern of EEG activity takes approximately 30 h and then the first sighns for spontaneous normalization appears. Spontaneous recovery from comatose state starts by restoration of light slow wave sleep EEG picture, taking approximately 40 h after lesioning. Serial electrical stimulations of dorsal, lateral, posterior and perifornical hypothalamic Orexin- containing neurons significantly speed up light slow wave sleep recovery, taking 30–35 h after comatose state. Deep slow wave sleep recovery was speed up by 13–15 h. Acceleration was also noted in forced restoration of passive and active wakefulness EEG picture. Significant elevation was noted in CSF OrexinA Concentration. Serial electrical stimulations of hypothalamic Orexin-containing neuronal regions significantly elevates CSF OrexinA concentration, speed up recovery from comatose state, and manifest in accelerated restoration of sleep-wakefulness cycle behavioral states. Supported by Shota Rustaveli National Science Foundation, Grant #11/04.